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Transcript of Fat
Fatty Acid Metabolism in Humans
Fat and Lean Interactions
Lean
Body
MassAdipose
tissue
Fatty Acid Metabolism in Humans
• Virtually all fatty acids originate from dietary
triglyceride fatty acids.
• Long-term storage site is adipose tissue.
• Regulated release of fatty acids as free fatty acids
provides the majority of lipid fuel for postabsorptive
adults.
Fatty Acid Metabolism in Humans
Oxidation
100 gm
TG fatty acids
Chylomicron TG
100 gmFFA
Direct Oxidation
CO2 + H2O(20-70 gm)
Adipose tissue
(30-80 gm)
FFA: free fatty acids
TG: triglycerides
Adipose PhysiologyInsulin
Adipocyte
Triglycerides
FFA
Glycerol
FFA: free fatty acids
Adipose PhysiologyInsulin
Adipocyte
Triglycerides
FFA
Glycerol
FFA: free fatty acids
Adipose PhysiologyGrowth hormone
catecholamines
Adipocyte
Triglycerides
FFA
Glycerol
FFA: free fatty acids
Adipose Physiology
Adipocyte
Triglycerides
FFA
Glycerol
Growth hormone
catecholamines
FFA: free fatty acids
Relationship Between Body Composition and Physiological Consequences
• Body fat distribution and free fatty acids (FFA)• Adipose tissue FFA release• Effects of excess FFA on health
Body Fat Distribution and Free Fatty Acids (FFA)
Normal FFA High FFA
Intra-abdominal (Visceral) Fat and Upper Body Obesity
Subcutaneous fat
Intra-abdominal fat
FFA
Upper Body / Intra-abdominal (Visceral) Obesity and Insulin Resistance
Insulin
resistance
Glucose
release
Constriction
Relaxation
Insulin
secretion
Muscle Vasculature
Liver Pancreas
Upper body /
Intra-abdominal obesity
Insulinresistance
Free Fatty Acids (FFA) and PancreasInsulin resistance FFA
• Long-term damage to
beta cells
• Decreased insulin
secretion
Short-term stimulation
of insulin secretion
Pancreas
Adipose tissue
Free Fatty Acids (FFA) and Dyslipidemia
Liver
VLDL-TG
HDL cholesterol
Apo B100 synthesis
and secretion
Insulin resistance FFA
Adipose tissue
TG: triglycerides
Free Fatty Acids (FFA) and Glucose Production
Insulin resistance FFA
Adipose tissue
Liver
Glucose release
Skeletal
muscle
cells
Free Fatty Acids (FFA) and Muscle
Intra-
muscular
TG
Insulin resistance
Glucose uptake
Muscle
Insulin resistance FFA
Adipose tissue
TG: triglycerides
Free Fatty Acids (FFA) and Hypertension
Relaxation – decreased nitric oxide generation
Vasculature
Constriction –
greater response
to alpha-
adrenergic stimuli
Insulin resistance FFA
Adipose tissue
Body Fat Distribution and Free Fatty Acids (FFA)
• Upper body obesity is associated with adverse metabolic consequences.
• Upper body obesity is associated with high basal and postprandial
FFA.
• Intra-abdominal (visceral) fat most strongly correlated with
metabolic abnormalities.
• Do the excess FFAs come from intra-abdominal fat?
Regional Adipose Tissue Model
Intra-abdominal
(visceral) fat
Lower body
subcutaneous fat
Upper body
subcutaneous fat
Summary
• Upper body subcutaneous fat accounted for the
majority of systemic free fatty acid (FFA) release.
• Intra-abdominal (visceral) fat mass correlated with
but was not the source of most systemic FFA release.
• Intra-abdominal fat mass predicts greater delivery of
FFA to the liver from intra-abdominal lipolysis.
• A greater portion of free fatty acid (FFA) appearance
derives from leg and splanchnic adipose tissue in
obese than lean men and women.
Cont….
• Nevertheless, the majority of systemic FFAs originate from upper
body subcutaneous fat in obese men and women.
• Intra-abdominal (visceral) fat correlates positively with the
proportion of hepatic FFA delivery from intra-abdominal fat in
both men and women.
• Upper body obesity is associated with high free fatty acids (FFA) due to excess release from upper body subcutaneous fat.
• High FFA can result in:
• insulin resistance in muscle and liver
• VLDL TG
• insulin secretion (?diabetes)
• Vascular abnormalities
Conclusions
• In both men and women, greater amounts of intra-
abdominal (visceral) fat result in a greater
proportion of hepatic free fatty acid (FFA) delivery
originating from intra-abdominal adipose tissue
lipolysis in the overnight postabsorptive state.
• This implies that arterial FFA concentrations will
underestimate hepatic FFA delivery systematically
and progressively with greater degrees of intra-
abdominal adiposity.
Cont…
• Fat is a dynamic and varied tissue.
• Regional differences in adipose biology affect health.
• The causes of differences in body fat distribution are unknown.
• The relative contributions of high free fatty acids and adipokines to adverse health is unknown.
Hyperlipidemia
• Hyperlipidemia Hyperlipoproteinemia means abnormally increased plasma lipoproteins-one of the risk factors for atherosclerosis (deposition of fats at walls of arteries, forming plaque)
• Other risk factors-Cigarette smoking, Diabetes, another source of oxidative stress. Also, obesity and, hypertension.
• Hyperlipemia denotes increased
levels of triglycerides.
• Such abnormality is extremely
common in general population,
regarded as highly modifiable
risk factor for cardio vascular
diseases, due to influence of
cholesterol.
INTRODUCTION
Plasma lipids include: cholesterols, triglycerides and phospholipids.Lipids are insoluble in plasma and are transported in protein capsule known as LIPOPROTEIN
Types of lipoproteins1. Chylomicrons (TGs): → formed in GIT from dietary
TG.
2. VLDL (TGs and cholesterol) → endogenously synthesized in liver. Degraded by LPL into free fatty acids (FFA) for storage in adipose tissue and for oxidation in tissues such as cardiac and skeletal muscle.
3. IDL (TGs, cholesterol); and LDL (cholesterol) → derived from VLDL hydrolysis by lipoprotein lipase.Normally, about 70% of LDL is removed from plasma by hepatocytes.
4. HDL (protective) →exert several anti atherogeniceffects. They participate in retrieval of cholesterol from the artery wall and inhibit the oxidation of atherogenic lipoproteins& removes cholesterol from tissues to be degraded in liver.
Composition Density Size
Chylomicrons TG >> C, CE Low Large
VLDL TG > CE
IDL CE > TG
LDL CE >> TG
HDL CE > TG High Small
Causes of Hyperlipidemia
• Diet
• Hypothyroidism
• Nephrotic syndrome
• Anorexia nervosa
• Obstructive liver disease
• Obesity
• Diabetes mellitus
• Pregnancy
• Obstructive liver disease
• Acute heaptitis
• AIDS (protease inhibitors)
Dietary sources of Cholesterol
Type of Fat Main Source Effect on
Cholesterol levels
Monounsaturated Olives, olive oil, canola oil, peanut oil,
cashews, almonds, peanuts and most
other nuts; avocados
Lowers LDL, Raises
HDL
Polyunsaturated Corn, soybean, safflower and cottonseed
oil; fish
Lowers LDL, Raises
HDL
Saturated Whole milk, butter, cheese, and ice cream;
red meat; chocolate; coconuts, coconut
milk, coconut oil , egg yolks, chicken skin
Raises both LDL and
HDL
Trans Most margarines; vegetable shortening;
partially hydrogenated vegetable oil; deep-
fried chips; many fast foods; most
commercial baked goods
Raises LDL
Hereditary Causes of Hyperlipidemia
• Familial Hypercholesterolemia
• Codominant genetic disorder, Occurs in heterozygous form
• Occurs in 1 in 500 individuals
• Mutation in LDL receptor, resulting in elevated levels of LDL at birth and
throughout life
• High risk for atherosclerosis, tendon xanthomas (75% of patients), tuberous
xanthomas and xanthelasmas of eyes.
• Familial Combined Hyperlipidemia
• Autosomal dominant
• Increased secretions of VLDLs
• Dysbetalipoproteinemia
• Affects 1 in 10,000
• Results in apo E2, a binding-defective form of apoE (which usually plays
important role in catabolism of chylomicron and VLDL)
• Increased risk for atherosclerosis, peripheral vascular disease
• Tuberous xanthomas, striae palmaris
Types of HyperlipidemiaFRERICKSON CLASSIFICATION- based on the pattern of
lipoprotein on electrophoresis or ultracentrifugation.
• Primary Chylomicronemia (I): Chylomicrons are not present in the serum of normal individuals who have fasted 10 hours. The recessive traits of deficiency of lipoprotein lipase or its cofactor are usually associated with severe lipemia.
• Familial Hypercholesterolemia (IIA): Familial hypercholesterolemia is an autosomal dominant trait. Although levels of LDL tend to increasewith normal VLDL.
• Familial Combined (mixed) Hyperlipoproteinemia (IIB):elevated levels of VLDL, LDL.
• Familial Dysbetalipoproteinemia (III): Increased IDL resulting increased TG and cholesterol levels.
• Familial Hypertriglyceridemia (VI): Increase VLDL production with normal or decreased LDL.
• Familial mixed hypertriglyceridemia (V): Serum VLDL and chylomicrons are increased
Diagnosis of hyperlipidemia
• Diagnosis is typically based on medical history, physical examination and blood test done after overnight fasting.
Management of Hyperlipidemias
I- Diet:
• Avoid saturated fatty acids (animal fats) and give unsaturated fatty acids (plant fats).
• - Regular consumption of fish oil which contains omega 3 fatty acids and vitamins E and C (antioxidants).
II. Exercise:
• - ↑ HDL and insulin sensitivity.
III- Drug therapy: the primary goal of therapy is to decrease levels of LDL . Also,increase in HDL is recommended.
Medications for Hyperlipidemia
Drug Class Agents Effects (% change) Side Effects
HMG CoA reductase
inhibitors
Lovastatin
Pravastatin
LDL (18-55), HDL (5-15)
Triglycerides (7-30)
Myopathy, increased liver
enzymes
Cholesterol
absorption inhibitor
Ezetimibe LDL( 14-18), HDL (1-3)
Triglyceride (2)
Headache, GI distress
Nicotinic Acid LDL (15-30), HDL (15-35)
Triglyceride (20-50)
Flushing, Hyperglycemia,
Hyperuricemia, GI distress,
hepatotoxicity
Fibric Acids Gemfibrozil
Fenofibrate
LDL (5-20), HDL (10-20)
Triglyceride (20-50)
Dyspepsia, gallstones,
myopathy
Bile Acid
sequestrants
Cholestyramine LDL
HDL
No change in triglycerides
GI distress, constipation,
decreased absorption of
other drugs
REFERENCE:
K.D.Tripathi, Essentials of Medical Pharmacology, 6th Edition, PgNo. 612-626.
Goodman & Gilman’s, The Pharmacological Basis Of Therapeutics, 11th
Edition, PgNo. 933-965.
INTERNET.